Inhibitors of the PI3K/Akt/mTOR Pathway in Prostate Cancer Chemoprevention and Intervention

Wang

J Cellular Molecular Medi

2021

HCLS1-associated protein X-1 (HAX1), an anti-apoptotic molecular, overexpresses in glioma. However, the role of HAX1 in glioma cell surviving in hypoxic environment remains unclear. Western blotting, qRT-PCR, Transwell assay, TUNEL assay, wounding healing assay, clone formation, tumour xenograft model and immunohistochemical staining were used to investigate the role of HAX1 in glioma. HAX1 regulated by HIF-1α was increased in glioma cells cultured in hypoxia. Silencing of HAX1 could cause an increased apoptosis of glioma cells cultured in hypoxia. Silencing of HAX1 also decreased the proliferation, migration and invasion of glioma cells cultured in hypoxia. Increased mitochondrial fission could prevent glioma cells from the damage induced by HAX1 knockdown in hypoxia. Furthermore, HAX1 was found to regulate glioma cells through phosphorylated AKT/Drp signal pathway. In conclusion, our study suggested that HAX1 promoted survival of glioma cells in hypoxic environment via AKT/Drp signal pathway. Our study also provided a potential therapeutic target for glioma.

Section: Discussionmentioning

confidence: 99%

HAX1 maintains the glioma progression in hypoxia through promoting mitochondrial fission

Wang

J Cellular Molecular Medi

2021

“…The phosphatase PTEN plays a negative modulator of mTOR cascade [81]. It inhibits the signaling through the PI3K-Akt pathway through the involvement of TSC1/2 [82]. Deregulation of various components of the mTOR pathway, such as PI3K amplification/mutation, loss of PTEN function, overexpression of Akt, ribosomal protein S6 kinase beta-1 (S6K1), eukaryotic translation initiation factor 4E binding protein 1 (4EBP1), and overexpression of eukaryotic translation initiation factor 4E (eIF4E), has been reported in numerous cancers, especially melanoma, where variation in key elements of the mTOR signaling have major effects on tumor growth [83].…”

Section: Inhibition Of Pi3k/akt/mtor Signaling Pathway By Different Flavonoidsmentioning

confidence: 99%

Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach

Zughaibi

Suhail

Tarique

et al. 2021

IJMS

Cancer is, globally, one of the main causes of death. Even though various therapies are available, they are still painful because of their adverse side effects. Available treatments frequently fail due to unpromising responses, resistance to classical anticancer drugs, radiation therapy, chemotherapy, and low accessibility to tumor tissues. Developing novel strategies to minimize adverse side effects, improve chemotherapy sensitivity, and control cancer progression is needed. Many studies have suggested small dietary molecules as complementary treatments for cancer patients. Different components of herbal/edible plants, known as flavonoids, have recently garnered attention due to their broad biological properties (e.g., antioxidant, antiviral, antimicrobial, anti-inflammatory, anti-mutagenic, anticancer, hepatoprotective, and cardioprotective). These flavonoids have shown anticancer activity by affecting different signaling cascades. This article summarizes the key progress made in this area and discusses the role of flavonoids by specifically inhibiting the PI3K/Akt/mTOR pathway in various cancers.

“…Mammalian target of rapamycin (mTOR) regulates a wide range of cellular events including cell proliferation, protein translation, metabolism, regeneration, autophagy, and apoptosis [ 16 , 17 , 18 ]. In the context of molecular mechanism, mTOR plays a central role coordinating ERBB (also known as EGFR/PI3K/AKT) and VEGF signaling in the ERBB/mTOR/VEGF axis, a signaling network frequently upregulated in PCa [ 19 , 20 , 21 , 22 ]. In this study, we particularly focused on the reciprocal pairing miR-99b-5p/ MTOR , where miR-99b-5p is downregulated while MTOR is upregulated in AA PCa compared to EA PCa.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of miR-99b-5p and Upregulation of Nuclear mTOR Cooperatively Promotes the Tumor Aggressiveness and Drug Resistance in African American Prostate Cancer

Gujrati

Waseem

et al. 2022

IJMS

Mammalian target of rapamycin (mTOR) regulates various fundamental cellular events including cell proliferation, protein synthesis, metabolism, apoptosis, and autophagy. Tumor suppressive miR-99b-5p has been implicated in regulating PI3K/AKT/mTOR signaling in a variety of types of cancer. Our previous study suggested the reciprocal miR-99b-5p/MTOR (downregulated/upregulated) pairing as a key microRNA-mRNA regulatory component involved in the prostate cancer (PCa) disparities. In this study, we further validated the expression profiles of mTOR and miR-99b-5p in the PCa, colon, breast, and lung cancer specimens and cell lines. The immunohistochemistry (IHC), immunofluorescence, Western blot, and RT-qPCR assays have confirmed that mTOR is upregulated while miR-99b-5p is downregulated in different patient cohorts and a panel of cancer cell lines. Intriguingly, elevated nuclear mTOR expression was observed in African American PCa and other advanced cancers. Transfection of the miR-99b-5p mimic resulted in a significant reduction in nuclear mTOR and androgen receptor (AR), while a slight/moderate to no decrease in cytoplasmic mTOR and AR in PCa and other cancer cells, suggesting that miR-99b-5p inhibits mTOR and AR expression and their nuclear translocation. Moreover, overexpression of miR-99b-5p targets/inhibits AR-mTOR axis, subsequently initiating cell apoptosis and sensitizing docetaxel-induced cytotoxicity in various cancers. In conclusion, our data suggest that reciprocal miR-99b-5p/nuclear mTOR pairing may be a more precise diagnostic/prognostic biomarker for aggressive PCa, than miR-99b-5p/MTOR pairing or mTOR alone. Targeting the AR-mTOR axis using miR-99b-5p has also been suggested as a novel therapeutic strategy to induce apoptosis and overcome chemoresistance in aggressive PCa.